Convection Enhanced Delivery
Many promising therapeutic agents for central nervous system (CNS) disorders have failed to attain clinical success due to the blood-brain barrier (BBB), which prevents the passage of agents from the systemic circulation into the brain. Systemic administration of high drug doses may increase delivery to the brain, but this approach risks significant side effects and toxicity. Direct delivery of drugs to the brain facilitates bypass of the BBB. However, the therapeutic efficacy of drugs injected into the brain parenchyma and/or tumours is limited by minimal diffusion from the site of injection and consequently, small volumes of distribution. In 1994, the concept of convection-enhanced (CED) delivery was introduced as a solution to these obstacles to therapeutic drug delivery to the CNS (Bobo R H, Laske D W, Akbasak A, Morrison P F, Dedrick R L, Oldfield E H, Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA, 91:2076-80 (1994); Morrison P. F., Laske D. W., Bobo H., Oldfield E. H., Dedrick R. L., High-flow microinfusion: tissue penetration and pharmacodynamics. Am J Physiol., 35: R292-305 (1994)).
CED describes continuous infusion of agents under pressure through neurosurgically-placed micro-catheters. This method has several potential advantages over conventional drug delivery methods. CED facilitates highly accurate anatomical targeting, delivery of higher (therapeutic) drug concentrations throughout clinically relevant volumes of brain tissue or tumour, and reduces systemic side effects. CED has been extensively investigated in the context of a wide range of CNS disorders in both pre-clinical and clinical trials—most notably for the treatment of brain tumours and Parkinson's disease.
Drugs can be administered directly to the brain in concentrations that would result in significant toxicity if given systemically. In contrast to delivery techniques that are dependent on diffusion, such as intraparenchymal injection, which leads to drug distribution heterogeneously over short distances down a concentration gradient; CED enables the controlled, homogeneous distribution of drugs over many centimeters of brain, regardless of the molecular size of the drug (Morrison et al.), Furthermore, as CED leads to the displacement of extracellular fluid with infusate, it offers an unparalleled opportunity to manipulate the extracellular environment of malignant brain tumours such as glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG).
CED has been investigated in the context of a wide range of brain disorders, in both pre-clinical and clinical trials—most notably for the treatment of Parkinson's disease or tumours at other sites within the brain. It has been shown to be safe, and effective in delivering agents to specific anatomical sites, and significant beneficial effects have been seen, including tumour response to chemotherapy, and re-growth of putaminal neurons leading to reversal of Parkinsonism.
Intermittent CED can be used to repeatedly administer drug by CED to the same target area without the need for further surgery. This is especially useful when treating malignant tumours, as repeated exposure to chemotherapy is essential to ensure that cells are adequately exposed to drug.
Histone Deacetylase Inhibition in CNS Disease
DNA and histones provide the main building blocks for nucleosomes, the structural units of chromatin that are important for packaging DNA. Changes in the structural configuration of chromatin to an active (open) or inactive (condensed) form alters the accessibility of DNA for transcription, ultimately affecting gene expression. One of the major ways that transcription factor binding to DNA is regulated is through changes in chromatin conformation, which in turn is governed by chemical modifications such as the acetylation and deacetylation of lysine residues of core nucleosomal histones. These changes are under the control of opposing activities of histone deacetylase (HDAC) and histone acetylase (HAT), and lead to altered gene expression, including genes involved in cell cycle regulation, differentiation and apoptosis. Acetylation is generally linked to an ‘open’ chromatin state that is ready for transcription or that corresponds to actively transcribed genomic regions, whereas deacetylation is associated with a closed or inactive state, leading to gene repression. The relative degree of histone acetylation and deacetylation therefore controls the level at which a gene is transcribed. HDAC also has crucial roles in cell cycle proliferation and apoptosis, including transcription factors such as p53, NF-jB and E2F1, which play key roles in tumorigenesis and anti-tumor response, as well as proteins that do not directly regulate gene expression but instead regulate DNA repair (Ku70), the cellular cytoskeleton (a-tubulin) and protein stabilisation (Hsp90). Notably, among non-histone HDAC substrates, Hsp90 plays a major role in the proper folding and stability of several major oncoproteins. HDAC activity also regulates cell protein turnover via the aggresome pathway, which if disrupted, results in the accumulation of polyubiquitinated misfolded protein aggregates, leading to cell stress and caspase-dependent apoptosis. These observations have extended the mechanism of anti-tumor activity of panobinostat and other HDAC inhibitors (HDACi) to include effects on non-histone proteins, implicated in multiple oncogenic pathways, in conjunction with epigenetic changes (Ataja, Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett. 280:233-241 (2009)).
As well as having anti-cancer properties, HDACi, such as panobinostat but also including sodium valproate, veronostat, trichostatin A and others, interact with the host immune system. They have been shown experimentally to promote the systemic cytokine and effector response of cytotoxic T cells and have far less efficacy in immunodeficient animals. Indeed, it seems that an intact immune system is necessary for their function (West, Smyth, Johnstone, The anticancer effects of HDAC inhibitors require the immune system. Oncoimmunology 3(1):e27414)(2014)). Panobinostat has immunoregulatory effects in patients with Hodgkin's lymphoma through the modulation of serum cytokine levels and T-cell co-stimulatory molecules such as PD-1. Panobinostat has also been reported to up-regulate MHC expression and sensitise tumour cells to immune-mediated cell death in malignant melanoma. HDAC inhibition may therefore be particularly effective in malignancies that are poorly immunogenic and are associated with an immunosuppressive microenvironment, such as malignant glioma. There is recent pre-clinical evidence in mice that combining systemic HDACi with systemic immune checkpoint blockade is particularly effective in a mouse model of metastatic disease (Kim, Skora, Li, Liu, Tam, Blosser, Diaz, Papadopoulos, Kinzler, Vogelstein, Zhou, Eradication of metastatic mouse cancers resistant to immune check point blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci USA 111:11774-9 (2014)).
It was found that water-soluble formulations of histone deacetylase inhibitors are particularly effective in treating CNS disorders when delivered directly to the brain by CED, especially when the CED is administered intermittently and/or in combination with chemotherapy or immunomodulatory agents.